Dopamine (DA) is an important neuromediator in central nervous system. The disbalance of DA nerves in brain may result in schizophrenia, Parkinson's disease, drug addiction and relapse, attention deficit or sexual dysfunction.
In 1990, Sokoloff et al found dopamine D3 receptor (D3R), and found it has 50% amino acid sequence homology in comparison with D2R, and further identified the specific typing of dopamine receptor. D3R is selectively distributed in marginal brain area, such as nucleus accumbens, Callejia island, olfactory tubercle. Some current research reports show that D3R is closely associated with many neurosises, such as schizophrenia, Parkinson's disease, drug dependence (or drug addiction), any forms of stress, anxiety, and somnipathy. In addition, D3R is associated with physiologic functions such as kidney function and immunoregulation.
In investigating the physiological functions of D3R and its correlation with central diseases, kidney dysfunction and immunological disorders, the research of D3R ligands is also a hotspot of drug studying. D3R ligands can be divided into D3R preferential ligands and D3R selective ligands according to their selectivity, or divided into D3R agonists, D3R partial agonists and D3R antagonists.
Currently, D3R ligands having relatively high affinity and selectivity have been disclosed in many technical reports. According to their chemical structure, the present D3R ligands mainly include 2-aminoindanes (WO95/04713), 2-aminotetrahydronaphthalenes (EP-A286516), tetrahydroisoquinolines (WO 97/43262, WO98/06699, U.S. Pat. No. 6,465,485 B1), benzoazepines (CN 01821985.3), dihydroindolines (U.S. Pat. No. 6,521,638B1), aryl piperazine derivatives (FR2878524), heterocyclic amides (EP 1749529), sulfonamides (US2007054918), benzothiophenes (WO95/10513), isoxazole derivatives (U.S. Pat. No. 6,673,800B2), substituted imidazoles (U.S. Pat. No. 6,358,955B1), triazoles (U.S. Pat. No. 6,602,867B1, WO2007022936), pyrimidinylpiperazine derivatives (CA2574827), etc. In general, there are groups of arylformamides, bioisosteres with arylformamido group, and 1,2,3,4-tetrahydronaphthalene-2-amine and analogs thereof, in which the group of arylformamides is the biggest group, in which the aryl can be of various types, the amino moiety can be mainly piperazine or tetrahydroisoquinoline, and amino can be linked to the arylformamido via four methylene groups or an equivalent linking chain (YANG Rifang, YUN Liuhong, “Advance in research of dopamine D3 receptor selective ligands, Progesses in Medicinal Chemistry 5, Edited by PENG Sixun, Chemical Industry Press, Beijing, 2007, pp 90-108).
Some D3R selective ligands show potential values for developing new drugs with D3R as the target in corresponding animal models and clinic trials. For example, Pramipexole (A Lieberman. Acta Neurol Scand, 2006, 113: 1), FAUC329 (F Boeckler, et al. Biochem Phamacol, 2003, 66(6): 1025), and BP897 (U.S. Pat. No. 5,872,119) disclose excellent neuroprotective effects in macaque model of Parkinson's disease; D3R preferential ligands S33138, A437203 (T Dubuffer, et al. Bioorg Med Chem Lett, 1999, 9(14): 2059; J F Joyce, M J Millan. Drug Disc Today, 2005, 10: 917) have entered phase II clinical test for treatment of schizophrenic; BP897 (C A Heidbreder. Curr Psychiatry Rev, 2005, 1: 45), SB277011A (C A Heidbreder, et al. Brain Res Rev, 2005, 49(1): 77) and NGB2904 (P Grundt, et al. J Med Chem, 2005, 48(13): 917) have been drawing many attentions in studying of drug addiction mechanism and development of drugs for treatment of drug addiction and relapse, in which BP897 as smoking deterrent is currently in phase II clinical test. Other reports mention that D3R agonist can be used for prevention of male sexual dysfunction (WO2003/051370, J Bragg, et al. Bioorg Med Chem Lett, 2007, 17: 6691).
Recent investigations indicate that D3R preferential ligands are more effective in prevention of drug abuse and relapse without exhibiting toxic and side effects of D2R ligands (Z-X Xi, et al. Neuropharmacology, 2007, 53: 771).
At present, there is still a need to search for novel compounds as dopamine D3 receptor ligands for clinical uses.